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DBL%20Hendrix%20small.png College chemistry, 1983

Derek Lowe The 2002 Model

Dbl%20new%20portrait%20B%26W.png After 10 years of blogging. . .

Derek Lowe, an Arkansan by birth, got his BA from Hendrix College and his PhD in organic chemistry from Duke before spending time in Germany on a Humboldt Fellowship on his post-doc. He's worked for several major pharmaceutical companies since 1989 on drug discovery projects against schizophrenia, Alzheimer's, diabetes, osteoporosis and other diseases. To contact Derek email him directly: derekb.lowe@gmail.com Twitter: Dereklowe

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April 8, 2010

ACC2: Great Metabolic Target, Or Total Bust?

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Posted by Derek

For people who've done work on metabolic disease, this paper in PNAS may come as a surprise, although there was a similar warning in January of this year. Acetyl CoA-carboxylase 2 (ACC2) has been seen for some years as a target in that area. It produces malonyl CoA, which is a very important intermediate and signaling molecule in fatty acid metabolism (and other places as well). A number of drug companies have taken a crack at getting good chemical matter (I'm no stranger to it myself, actually). A lot of the interest was sparked by reports of the gene knockout mice, which seem to have healthy appetites but put on no weight. The underlying reason was thought to be that fatty acid oxidation had been turned up in their muscle and adipose tissue - and a new way to burn off excess lipids sounded like something that a lot of people with excess weight and/or dyslipidemia might be able to use. What's more, the ACC2 knockout mice also seemed to be protected from developing insulin resistance, the key metabolic problem in type II diabetes. An ACC2 inhibitor sounds like just the thing.

Well, this latest paper sows confusion all over that hypothesis. The authors report having made some selective ACC2 knockout mouse strains of their own. If the gene is inactivated only in muscle tissue, the animals show no differences at all in body weight, composition, or food intake compared to control mice. What's more, when they went back and inactivated ACC2 in the whole animal, they found the same no-effect result, whether the animals were fed on standard chow or a high-fat diet. The muscle tissue in both cases showed no sign of elevated fatty acid oxidation. The authors state drily that "The limited impact of Acc2 deletion on energy balance raises the possibility that selective pharmacological inhibition of Acc2 for the treatment of obesity may be ineffective."

Yes, yes, it does. There's always the possibility that some sort of compensating mechanism kicked in as the knockout animals developed, something that might not be available if you just stepped into an adult animal with an inhibiting drug. That's always the nagging doubt when you see no effect in a knockout mouse. But considering that those numerous earlier reports of knockout mice showed all kinds of interesting effects, you have to wonder just what the heck is going on here.

Well, the authors of the present paper are wondering the same thing, as are, no doubt, the authors of that January Cell Metabolism work. They saw no differences in their knockout animals, either, which started the rethinking of this whole area. (To add to the confusion, those authors reported seeing real differences in fatty acid oxidation in the muscle tissue of their animals, even though the big phenotypic changes couldn't be replicated). Phrases like "In stark contrast to previously published data. . ." make their appearance in this latest paper.

The authors do suggest one possible graceful way out. The original ACC2 knockout mice were produced somewhat differently, using a method that could have left production of a mutated ACC2 protein intact (without its catalytic domain). They suggest that this could possibly have some sort of dominant-negative effect. If there's some important protein-protein interaction that was wiped out in the latest work, but left intact in the original report, that might explain things - and if that's the case, then there still might be room for a small molecule inhibitor to work. But it's a long shot.

The earlier results originated from the lab of Salih Wakil at Baylor (who filed a patent on the animals), and he's still very much active in the area. One co-author, Gerry Shulman at Yale, actually spans both reports of ACC2 knockout mice - he was in on one of the Wakil papers, and on this one, too. His lab is very well known in diabetes and metabolic research, and while I'd very much like to hear his take on this whole affair, I doubt if we're going to see that in public.

Comments (14) + TrackBacks (0) | Category: Biological News | Diabetes and Obesity


COMMENTS

1. SteveM on April 8, 2010 9:19 AM writes...

I'm a chemist but not a medicinal chemist. Here's a real question:

How does the "high metabolism" theory of any weight loss strategy jibe with simple thermodynamics? If metabolism is increased by a drug then the excess heat generated has to go somewhere. Do subjects on those agents actually have a higher body temperature?

If body temperature remains constant, the only way that a "metabolism increasing" drug could work, would be by either decreasing caloric absorption or decreasing caloric utilization. In either case, calories are not metabolized out thermodynamically, but rather eliminated as waste.

How do I have it wrong?

Permalink to Comment

2. Anonymous on April 8, 2010 10:10 AM writes...

I think that was how dinitrophenol worked. The patients sometime needed to be cooled down with ice.

A reverse question would be if a drug increases body temperature, does it also increase metabolism?

Permalink to Comment

3. Daniel Newby on April 8, 2010 10:25 AM writes...

SteveM: Evaporative and convective cooling of the skin is automatically adjusted to maintain a fairly constant core temperature.

Anonymous #2: Many drugs, such as atropine, increase body temperature by blocking sweating. I would expect metabolism to decrease to some extent, depending on how much energy was being liberated beforehand just to maintain temperature.

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4. partial agonist on April 8, 2010 10:46 AM writes...

Steve M: at least some things that ramp up metabolism also increase core body temperature. Amphetamine is one example.

Amphetamine ramps up metabolism AND it decreases appetite drastically, so it would be great for weight loss except for all of the other bothersome aspects like abuse potential, effects on heart rate, anxiety, insomnia, etc.

I don't think that there is a free lunch to weight loss (pun intended). You can decrease caloric intake or you can ramp up metabolism, and metabolic effects are sure to have unintended consequences.

I hope somehow to be wrong about that. Maybe if we understand, for example, how cells adapt in very positive ways to calorie-resticted diets we can somehow fool them into thinking that we are eating brocolli and not cheeseburgers, but I am a skeptic as to it working in humans. Rodents are another story. Energy intake in primates seems to be evolutionarily wired with multiple mechanistic redundancies that evolved in a food-scarce world.

Permalink to Comment

5. Cloud on April 8, 2010 10:53 AM writes...

partial agonist- I think you're right about the free lunch, or lack thereof. I think the best we can hope for is a drug that would help a motivated dieter short-circuit some of the mechanisms in the body that fight to keep weight on. So, you'd still have to change your diet and exercise, but your body would stop seeing that as a starvation signal.

But it has been awhile since I was involved in this area of research, so maybe I'm wrong.

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6. SteveM on April 8, 2010 10:59 AM writes...

Thanks all for the info.

Daniel, your heat channeling explanation makes sense. But I guess the subject would be constantly sweating bullets.

Or perhaps the users could be trained to pant like dogs...

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7. mad on April 8, 2010 11:16 AM writes...

Stuff like this makes me worry that its sloppy science...the 2222 effect. The result of too many postdocs being pays too little for too long with no place to go!

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8. retread on April 8, 2010 12:36 PM writes...

Both ACCs are very complicated proteins and genes. Both contain over 2300 amino acids, implying that something this large is interacting with lots of things in the cell (active sites just require that many amino acids). -- Actually this may be a general principle which I've not seen stated anywhere else. Fatty acid synthase is this large but it does have multiple active sites.

At least 7 alternatively spliced exons are known (out of 64 exons total), along with 3 different promoters, so anything translated from a 'knocked out' gene is likely to still have multiple interaction effects, even if catalytically inactive.

Derek: If you and your wife are up for dinner Saturday night in Cambridge, EMail me today. We leave for the holy land early tomorrow.

Permalink to Comment

9. lewis robinson on April 8, 2010 12:52 PM writes...

Sorry -- left out an important word -- here's the correct version

Both ACCs are very complicated proteins and genes. Both contain over 2300 amino acids, implying that something this large is interacting with lots of things in the cell (active sites just DON"T require that many amino acids). -- Actually this may be a general principle which I've not seen stated anywhere else. Fatty acid synthase is this large but it does have multiple active sites.


Permalink to Comment

10. barry on April 8, 2010 1:09 PM writes...

It is the first experiment--blocking the catalytic function without blocking the expression of ACC protein--that better models small-molecule blockade. If that experimental result can be replicated, ACC is a legitimate small-molecule target. We often rush to equate a genetic knock-out with small-molecule blockade of an enzyme. That's a legitimate simplipication when the protein has only one role. We don't know how often that's the case.

Permalink to Comment

11. C-drug on April 8, 2010 11:36 PM writes...

Partial agonist- Surely food scarcity has affected the evolution of rodents just as much as primates? I don't doubt that there are differences in the mechanisms, but do primates actually cling more strongly to their fat reserves than rodents do?

Permalink to Comment

12. Rafi Allos on April 9, 2010 5:24 AM writes...

ACC2 inhibition: the fact that simply increasing fatty acid oxidation in the absence of a negative energy balance does not have a weight/fat reducing effect does not mean that such increased FAO cannot have other favourable metabolic effects.

One possibility, depending on the hypothesis that you subscribe to with regards to the mechanism by which insulin resistance develops, is that a preferential increase in FAO will lead to decreased lipotoxicity due to decreased ectopic lipid deposition. This assumes that the decreased carbohydrate oxidation that would be a consequence will not simply lead to increased de novo lipogenesis and therefore ectopic lipid deposition from the end products of the DNL.


Increases in metabolism: DNP does lead to icnreased proton leak and an increase in core body temperature that if not carefully managed can lead to fatal hyperthermia.

However, would it not be possible to increase energy consuming processes in a futile manner that would not have such an adverse impact on temperature? Just thinking off the top of my head: an increase in protein turnover (without shifting protein balance) or an increase esterfication of fatty acids into triglycerides in adipose tissue and then de-esterfication? Such an increase in a futile cycle activity would lead to increased energy consumption.

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13. partial agonist on April 9, 2010 10:02 AM writes...

c-drug,

I draw the distinction between rodents and humans since there are piles and piles of obesity-related targets that had seemingly good small molecules that worked well in rodent models and then did nothing or next to nothing in humans. See leptin, NPY, CCK, beta 3, and a half dozen more at least. We have a lot more cross-talk between our appetite-regulating and energy-expediture pathways, for some reason (and I don't have a clue why that should be so).

Permalink to Comment

14. Anonymous on April 26, 2010 4:53 AM writes...

Producing futile energy consumption is a bass ackwards way of attacking the problem. In fact, amphetamine is an example of the better strategy, which is decreasing appetite and so using "higher level" controls to reduce energy input.

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